Certain benzothiazoles used in the treatment of helminthiasis

ABSTRACT

A novel treatment of helminthiasis is provided by means of the administration of specified benzothiazoles.

This application is a continuation-in-part of my copending applicationSer. No. 381,112 filed July 18, 1973, now abandoned.

This invention relates to the use of a small class of carbamate estersof benzothiazoles which are particularly effective anthelmitic agents,and to pharmaceutical formulations, especially oral dosage forms,containing the same.

These benzothiazoles have the general formula: ##STR1## wherein Y isethoxy or n-propoxy and R is methyl or ethyl.

Thus, this formula includes the following four compounds:

Ethyl-6-ethoxybenzothiazole-2-carbamate;

Ethyl-6-n-propoxybenzothiazole-2-carbamate;

Methyl-6-ethoxybenzothiazole-2-carbamate; and

Methyl-6-n-propoxybenzothiazole-2-carbamate.

The preferred compound for use in the invention ismethyl-6-n-propoxybenzothiazole-2-carbamate, which is a novel substance.

Compounds of the above formula are generically known in the art; as forexample U.S. Pat. Nos. 3,555,157 and 3,725,428 and the Journal of thePharmaceutical Society of Japan, Vol. 69, pgs. 398-400 (1949). The priorart describes the use of such benzothiazoles as horticulturalmicrobiocides, and in particular fungicides, but their anthelminticactivity had apparently not been known. While the prior art does teachthe anthelmintic activity of corresponding benzimidazoles, e.g.oxibendazole, such general correspondence neither is recognized in theart nor does in fact exist. For example, mebendazole (Y is benzoyl, R ismethyl) is a leading and highly effective anthelmintic. However, itsbenzothiazole analog has little or no anthelmintic activity.

The compounds of this invention may be prepared according to knownprocesses, e.g. as described in the above references. Five applicablemethods are described below (in each Y and R are as above defined)##STR2## wherein Z₁ is a reactive labile group such as halogen. Theprocess is preferably carried out in a suitable solvent such as pyridineat a reduced temperature, i.e. between 0° C and room temperature. Theformate is added slowly to amine-containing solvent with stirring. Thedesired carbamate is then isolated according to techniques well known inthe art. Purification can be effected by recrystallization in the usualmanner. Although pyridine is the preferred solvent for this reaction,other solvents such as acetonitrile and triethylamine and mixtures ofacetonitrile and pyridine may also be used. ##STR3## wherein Z₂ and Z₃are reactive labile groups such as --SCH₃, --OCH₃ or --N(CH₃)₂.

The reaction is preferably carried out by stirring and heating thereactants at reflux temperature in a suitable solvent such as ethanol,keeping the reaction mixture under an inert atmosphere, preferablynitrogen. ##STR4##

Also this process is carried out using standard techniques. Onepreferred method comprises heating the thiourea compound in a suitablesolvent such as chloroform at reflux temperature in the presence ofbromine. Instead of heating, one may also irradiate the reactionmixture. The isolation of the product is also performed according tostandard procedures. The mixture is brought to room temperature, washedwith aqueous Na₂ CO₃, and aqueous NaCl and dried over sodium sulfate.The solvent is removed by evaporation to yield the desired product. Theintramolecular cyclization may also be accomplished by adding an aqueoussolution of potassium ferricyanide to a stirred and moderately heatedmixture of the thiourea compound, sodium hydroxide and water. After theaddition of potassium ferricyanide is completed, potassium carbonate isadded and the stirring is continued. The reaction mixture is thenextracted with a suitable solvent, preferably chloroform. The extractsare dried over sodium sulfate and the solvent is evaporated to yield thedesired product. ##STR5##

The etherification is preferably carried out by heating a mixture of thehydroxybenzothiazole-2-carbamate, anhydrous potassium carbonate,n-propylbromide and a suitable solvent, e.g. acetone, at refluxtemperature. The solvent is then removed by distillation, the residuetaken into water and filtered. The pure product is obtained byrecrystallization from ethanol.

5. A further process comprises reacting a benzothiolzole-2-isocyanate ofthe general formula ##STR6## or a reactive derivative thereof withmethanol or ethanol. The reaction is preferably carried out by stirringa mixture of the anhydrous reactants in a solvent such as an excess ofalkanol, or benzene, at room temperature. The preferred reactivederivatives of the compounds of formula X are those wherein the group--N=C=O is replaced by the grouping ##STR7##

The appropriate starting compounds in the above processes 1 to 4 may beobtained by techniques well known in the art. The 2-amino-benzothiazolesmay be obtained by cyclizing the appropriate aniline with an alkalimetal isothiocyanate (MSCN) and cupric chloride in an acidic solventsuch as acetic acid. ##STR8##

The following examples serve to exemplify the above described processes.Examples 1 and 2 illustrate the preferred process and Examples 3 to 6illustrate alternative processes.

EXAMPLE 1 Preparation of methyl-6-n-propyloxybenzothiazole-2-carbamate

To a stirring solution of 24.45 g. of2-amino-6-n-propyloxybenzothiazole-hydrochloride in 100 ml of pyridinemaintained at 0° C. by an ice bath, is slowly added 9.45 g. of methylchloroformate. After the addition is completed the mixture is allowed towarm up to room temperature. It is then poured on 300 g. of ice water. Asolid is formed which is isolated by filtration and crystallized fromethanol yield 20 g m.p. 178°-180° C.

EXAMPLE 2 Preparation of ethyl-6-n-propoxybenzothiazole-2-carbamate

To a chilled solution of 10.4 g. 2-amino-6-n-propoxybenzothiazole in 50ml dry pyridine is dropwise added 6 g. ethyl chloroformate withstirring. The mixture is then allowed to stand at room temperature for 8hrs. It is poured in 200 g. of ice water and stirred for 30 mins. Thewhite solid product is separated by filtration and dried.Crystallization from ethanol gave 12 g. of the product. m.p. 175°-177°C.

EXAMPLE 3 Preparation of methyl-6-n-propoxybenzothiazole-2-carbamate

In a round bottom 1 liter flask equipped with a reflux condenser, amagnetic stirrer and a heating mantle is placed 45.75 g. of2-mercapto-4-propoxyaniline; 48.25 g. ofmethyl-N-[di(methylthio)-methylene] carbamate, and 250 ml absoluteethanol. This mixture is heated to boiling under an inert atmosphere ofnitrogen for 12 hrs. It is then chilled and the white crystalline solidwhich is formed is isolated by filtration, washed with cold ethanol anddried. m.p. 178°-180° C.

EXAMPLE 4 Preparation of methyl-6-n-propoxybenzothiazole-2-carbamate

A solution of 28.2 g. 1-carbomethoxy-3-(n-propoxyphenyl) thiourea and 16g. bromine in 700 ml of chloroform is irradiated in a quartz vessel by a450 W medium pressure mercury lamp until the color of brominedisappears. The reaction mixture is then washed with a 5% aqueous sodiumhydroxide solution, dried over anhydrous sodium sulfite, and the organicsolvent is evaporated to give a solid which is crystallized from ethanoland yields 26 g. of the desired compound. m.p. 178°-180° C.

EXAMPLE 5 Preparation of methyl-6-n-propoxybenzothiazole-2-carbamate

To a stirred suspension of 2.2 g. 1-carbomethoxy-3-(p-n-propoxyphenyl)thiourea in a solution of 2.42 g. sodium hydroxide in 35 ml of water, inan erlenmeyer flask at 64° (by water bath) is added a solution of 8.8 g.potassium ferricyanide in 20 ml water. The stirring is continued for 2additional hrs. Potassium carbonate, 6 g. is then added to this reactionmixture and stirring is continued for another 2 hr. period. It is thenextracted by 2 × 50 ml chloroform. The chloroform extracts are driedover anhydrous Na₂ SO₄ and the solvent is removed by evaporation to give2 g. of the product. m.p. 178°-180° C.

EXAMPLE 6 Preparation of methyl-6-n-propoxybenzothiazole-2-carbamate

A mixture of 11.5 g. anhydrous 6-n-propoxybenzothiazole-2-isocyanate, 5g. anhydrous methanol and 50 ml benzene is stirred at room temperaturefor 4-5 hours, is then poured into ice water and stirred for 30 minutes.The white solid product is isolated by filtration and recrystallizedfrom ethanol. m.p. 178°-180° C.

By using the appropriate starting compounds in the above processes onemay analogously prepare

methyl-6-ethoxybenzothiazole-2-carbamate and

ethyl-6-ethoxybenzothiazole-2-carbamate.

The compounds of this invention are useful in treating humans andanimals suffering from helminthiasis, i.e. an infestation of thegastrointestinal tract with parasitic worms, by administering to thehost animal a therapeutic amount thereof. These compounds combine a highdegree of anthelmintic activity with low host toxicity, i.e. a hightherapeutic index. Moreover, the anthelmintic activity is broadspectrum. They are effective against the four most prevalent nematodesknown to infest mammals, i.e. the compounds exhibit an effectiveanthelmintic effect against worm types such as S. Obvalata (pinworm),Ascaridae (roundworm), Ancylostomatidal (hookworm) and Trichuris(whipworm). For example, in the horse the preferred compound of thisinvention exhibits potent activity against large strongylest, e.g. S.vulgaris, S. edentatus and S. equinus; small strongyles, Oxyuris equiand P. equorum.

The anthelmintic activity of the subject compounds is evaluatedaccording to standard techniques such as the Modified McMaster EggCounting Technique as described by H. B. Whitlock and H. McL. Gordon: J.Council Scientific Industrial Research (Australia) 12: p. 50, 1939 andH. B. Whitlock: J. Council Scientific Research (Australia) 21: p. 177,1948. From these and similar tests anthelmintic efficiency is assessedby determining the number of eggs in faeces passed on the days followingtreatment with the compounds.

From such tests it is determined that the compounds of this inventionexhibit significant anthelmintic effects when administered to aninfested host (e.g. a horse) in the dose range of 30-100 mg/kg per day.Single or multiple dosing is contemplated using standard art techniques.The compounds of this invention are preferably orally administered inthe standard oral dosage forms such as tablets, boluses, capsules,elixirs, drenches or as feed additives. In addition, the compounds mayalso be used as injectible anthelmintic preparations. For this purposethe active ingredients are admixed with suitable sterile carriers suchas sterile water and isotonic saline solution.

The following examples illustrate typical formulations:

    __________________________________________________________________________    A:                                                                              Tablet formulation  Grams per 1000 tablets                                  __________________________________________________________________________    Methyl-6-n-propoxybenzothiazole-                                              2-carbamate           200.0                                                   Lactose               90.0                                                    Dicalcium phosphate, hydrous                                                                        122.5                                                   Polyvinylpyrolidone   25.0                                                    Polyethylene glycol 1500                                                                            7.5                                                     Corn Starch           50.0                                                    Magnesium Stearate    5.0                                                                           500.0                                                   __________________________________________________________________________

Mix the carbamate, the lactose and the dicalcium phosphate. Dissolve thepolyethylene glycol 1500 and the polyvinylpyrolidone in approximately 20ml of water. Granulate the powder blend with the water solution, addingadditional water if necessary, to produce a damp mass. Pass the wetgranulation through a 12 mesh screen; spread on trays and air dry at 35°C. Blend the dry granulates with the starch and the magnesium stearate.Compress into 500 mg. tablets.

    __________________________________________________________________________    B:                                                                              Capsule formulation Grams per 1000 capsules                                 __________________________________________________________________________    Methyl-6-n-propoxybenzothiazole-                                              2-carbamate           200.0                                                   Lactose               198.0                                                   Magnesium Stearate    2.0                                                                           400.0                                                   __________________________________________________________________________

Blend the ingredients and fill into hard gelatine capsules.

    ______________________________________                                        C:  Elixir formulation       Per 1000 ml                                      ______________________________________                                        Methyl-6-ethoxybenzothiazole-                                                 2-carbamate             40      g.                                            Sugar                   500     g.                                            Glycerin                200     g.                                            Compound Orange Spirit  10      ml                                            Alcohol                 100     ml                                            Amaranth                0.1     ml                                            Sodium Citrate          10      g.                                            Water to total          1000    ml                                            ______________________________________                                    

What is claimed is:
 1. A method of treating helminthiasis in mammalswhich comprises administering to a mammal suffering therefrom ananthelmintically effective quantity of a benzothiazole of the formula##STR9## wherein Y is ethoxy or n-propoxy and R is methyl or ethyl.
 2. Amethod according to clam 1 wherein R is methyl.
 3. A method according toclaim 1 wherein R is ethyl.
 4. A method according to claim 1 wherein Yis n-propoxy.
 5. A method according to claim 4 wherein R is methyl.
 6. Amethod according to claim 1 wherein said administering is effectedorally.